The present invention relates to therapeutic agents for osteoarthritis comprising mercaptoacylcysteine derivatives as active ingredients.
Osteoarthritis (OA) is a disease characterized by destruction of a joint accompanied by degeneration of cartilage in a joint due to aging and progressive degradation due to mechanical stress, and by a proliferative change of bone cartilage.
A diseased part of osteoarthritis is limited to the joint, mainly a load joint. Unlike systemic autoimmune diseases such as rheumatic diseases, a synovial fluid of osteoarthritis is noninflammatory. Abnormal remarks are scarcely observed in its peripheral blood, generally an erythrocyte sedimentation rate value and a CRP value are normal, and a rheumatic factor is negative.
With regard to pathogeneses of osteoarthritis, various possibilities have been suggested by previous studies.
One of them is a lowering of an essential function of cartilage due to a decrease in chondrocytes, partial softening of chondromucoid, a decrease in water content in a cartilage substrate or a change in collagen reticular structure with aging, or a lowering of collagen synthesis due to a lowering of sensitivity of chondrocytes to transforming growth factor xcex2 (TGF-xcex2), which plays an important role in chondrocytes (Arthritis Rheum., 40, 1275-1281 (1997)).
On the other hand, production of matrix metalloproteinase (MMP) from chondrocytes advances owing to imbalance of a joint or mechanical stress on chondrocytes due to various causes or by cytokines such as interleukin-1xcex2 (IL-1xcex2), and MMP degrades a matrix to cause cartilage denaturation. Actually, it is considered that MMP production from cartilage tissues of patients with osteoarthritis or experimental chondrocytes is a main cause of osteoarthritis. In particular, it is known that MMP-1 and MMP-8 not only degrade collagen but also activate a variety of gelatinase, which degrades collagen completely. Further, it was reported that MMP-3 has degradative activity on proteoglycan, collagen and link protein, which play important roles in cartilage tissues, and MMP-3 exhibits the activity strongly in patients with osteoarthritis and model animals as well (Osteoarthr. Car., 6, 286-294 (1998)).
Further, as third pathogenesis, it was recently reported that chondrocytes death due to apoptosis of chondrocytes by stress, cytokines, nitric oxide (NO) or the like participates in osteoarthritis (Arthritis Rheuma., 41, 284-289 (1998)).
It was reported that mercaptoacylcysteine derivatives, which are active ingredients of the present invention, have various actions as medicines. Examples of the action are a sputum dissolving action (Japanese Examined Patent Publication No. 5388/1981), an antirheumatic action (Japanese Examined Patent Publication No. 11888/1985), a cataract therapeutic action (Japanese Examined Patent Publication No. 13922/1987), a liver disorder inhibitory action (Japanese Examined Patent Publication No. 13964/1988), an uveitis therapeutic action (Japanese Laid-open Patent Publication No. 96521/1990), a diabetes therapeutic action (Japanese Laid-open Patent Publication No. 154721/1992), an osteoporosis therapeutic action (Japanese Laid-open Patent Publication No. 154722/1992), a kidney disease therapeutic action (Japanese Laid-open Patent Publication No. 342524/1992), a cystinuria therapeutic action (Japanese Laid-open Patent Publication No. 186341/1993), an inflammatory enteropathy therapeutic action (Japanese Laid-open Patent Publication No. 223944/1995), a delayed allergy inhibitory action (Japanese Laid-open Patent Publication No. 158160/1998), an endothelium growth factor inhibitory action (Japanese Laid-open Patent Publication No. 324625/1998), a corneal neovasculature proliferation inhibitory action (Japanese Laid-open Patent Publication No. 712272/1999) and the like. Among them, bucillamine has already been marketed as pharmaceuticals, and its pharmaceutical utility has already been proved. However, there has been no report concerning its action on osteoarthritis.
It is a very interesting subject to find further new pharmacological actions of these mercaptoacylcysteine derivatives being useful as pharmaceuticals.
In order to find new pharmacological actions of mercaptoacylcysteine derivatives, the present inventors studied their actions on MMP-3 production of chondrocytes and degradation of proteoglycan as actions on cartilage of a joint. As a result, it was found that these mercaptoacylcysteine derivatives have MMP-3 production inhibitory actions and proteoglycan degradation inhibitory actions and are useful as therapeutic agents for diseases in which MMP participates, particularly osteoarthritis. It is known that arthrogryposis occurs and a mobility of a joint decreases in patients with osteoarthritis. Then, effects of the mercaptoacylcysteine derivatives on arthrogryposis were evaluated by using rabbit-immobilized models. As a result, a high improvement effect was found also in these rabbit-immobilized models.
The present invention provides therapeutic agents for osteoarthritis comprising compounds represented by the following general formula [I] or salts thereof (hereinafter referred to as xe2x80x9cthe present compoundxe2x80x9d) as active ingredients, 
wherein xe2x80x9cAxe2x80x9d is lower alkylene.
The group defined above is described in more detail. The lower alkylene is straight-chain or branched alkylene having one to six carbon atoms such as methylene, ethylene, (dimethyl)methylene or (diethyl)methylene.
Salts in the present invention refer to any pharmaceutically acceptable salts. Examples thereof are salts with an alkali metal or an alkaline-earth metal such as sodium, potassium or calcium; ammonium salts; salts with an organic amine such as diethylamine or triethanolamine; and the like. The present compounds can be in the form of hydrates. There are diastereo isomers and optical isomers in the present compounds, and all of them are included in the present invention. When an optically active starting material for synthesis is used, a single diastereo isomer and a single optical isomer are obtained. When a racemate is used as a starting material, respective isomers can be separated by conventional methods, for example, a method of using an optical resolving agent or the like.
A particularly preferred example of the present compound is bucillamine represented by the following formula [II]. 
The actions of the present compounds on cartilage of the joint are described in Examples in detail. It was recognized that the present compounds have the MMP-3 production inhibitory actions and the proteoglycan degradation inhibitory actions. Accordingly, it was suggested that the present compounds are useful as the therapeutic agents for the diseases in which MMP participates, particularly osteoarthritis.
Arthrogryposis occurs in the patients with osteoarthritis. Studying improvement effects of the present compounds on a mobility of a joint by using the rabbit-immobilized models, apparent improvement effects were recognized.
As described in the section of xe2x80x9cBackground Artxe2x80x9d, it is already known that the present compounds are useful as therapeutic agents for rheumatic diseases. However, osteoarthritis is a disease characterized by destruction of a joint accompanied by degeneration of cartilage in a joint due to aging and progressive degradation due to mechanical stress, and characterized by a proliferative change of bone cartilage, and differs from systemic autoimmune diseases such as the rheumatic diseases. Osteoarthritis differs from the rheumatic diseases also in that a synovial fluid is noninflammatory, abnormal remarks are scarcely observed in its peripheral blood, generally an erythrocyte sedimentation rate value and a CRP value are normal, and a rheumatic factor is negative.
Administration methods of drugs can be a method of administering the present compounds themselves as active compounds or a method of administering the present compounds in the form to be decomposed in vivo and to be converted into the active compounds, namely in the form of prodrugs. Both are widely used. The present compounds contain one carboxyl group and two thiol groups in their molecule. The present compounds themselves can be administered as active compounds, and the present compounds can be also administered with the above-mentioned groups protected with suitable protecting groups which can be converted into the active compounds in vivo, namely in the form of so-called prodrugs.
The present compound can be administered orally or parenterally. Examples of dosage forms are tablets, capsules, granules, powders, injections and the like. The present compound can be formulated into preparations by the conventional methods. For example, oral preparations such as tablets, capsules, granules and powders can be produced by adding optionally a diluent such as lactose, crystalline cellulose, starch or vegetable oil; a lubricant such as magnesium stearate or talc; a binder such as hydroxypropylcellulose or polyvinyl pyrrolidone; a disintegrator such as calcium carboxymethylcellulose or low-substituted hydroxypropylmethylcellulose; a coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or a film forming agent such as a gelatin film.
The dosage of the present compound can be selected suitably depending on symptoms, age, dosage form and the like. In case of the oral preparations, the present compound can be administered once to several times per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000 mg.
Results of pharmacological tests are shown below. These do not limit the scope of the invention, but are intended to make the invention more clearly understandable.